Research Highlights - Spring 2016

Study offers clues to precision treatments for leukemia

One of the biggest success stories in pediatric oncology is the effort to cure acute lymphoblastic leukemia (ALL). Survival rates for ALL, the most common childhood cancer, have risen above 90 percent. However, survival remains poor for children with treatment-resistant forms of the disease.

Enter a possible game-changer: A new study led by St. Jude on a tough-to-treat form of ALL called Ph-like ALL. In revealing genetic secrets of the disease, the study has identified promising treatment options in existing drugs.

Cancer cells in this form of ALL have a broken chromosome that gets put back together incorrectly. The study revealed not one, but four, similar rearrangements of the chromosome occurring in different patients. The rearrangements created a shortened version of a gene called EPOR. All led to the same thing: white blood cells proliferating out of control.

Now for the good news: the researchers were able to counter the out-of-control biological processes triggered in Ph-ALL using an existing drug called ruxolitinib. In laboratory experiments, ruxolitinib also enhanced the function of other chemotherapy drugs.

“We think these findings provide a useful road map for planning more accurate testing of combination chemotherapies,” Mullighan said. In fact, one such clinical trial will take place at St. Jude.

Promising drug tames immune system

The immune system is built to protect the body. But an overactive immune system can do just the opposite. For patients with hemophagocytic lymphohistiocytosis (HLH), extreme immune activity can cause life-threatening inflammatory reactions.

If standard treatment fails, patients are left with few choices. Now, a promising new option has emerged from a study led by St. Jude Children’s Research Hospital.

In patients with HLH, a massive buildup of white blood cells can cause a “cytokine storm,” which triggers a dangerous inflammatory reaction. By recreating this scenario in the lab, researchers were able to search for drugs that reduced inflammation.

The scientists homed in on molecules called JAKs, which enable cytokines to carry out their normal functions. “We reasoned that inhibition of these JAKs might diminish inflammation and lessen disease,” said Kim Nichols, MD, of St. JudeOncology.

They were right. Inhibiting JAK function with a drug called ruxolitinib reduced both inflammation and its negative biological effects. Since ruxolitinib has been well studied for many years in the treatment of other conditions, it is an attractive candidate for clinical trials for HLH.

“It is our hope that by incorporating JAK inhibitors, we can improve the cure rate for children and adults suffering from this devastating and often life-threatening disorder,” noted Nichols. The study was published in the journal Blood.

Parental influence extends to drug response

Doctors know patients sometimes respond very differently to the same drug. St. Jude Children’s Research Hospital is a leader in studying how differences in the makeup of the genes inherited from each parent influence how patients react to certain drugs. St. Jude is also a pioneer in using the information to guide clinical care.

An international research team led by St. Jude scientists has discovered how such inherited differences can cause serious problems during leukemia treatment.

The scientists showed that patients who inherit certain versions of a gene named NUDT15 were more sensitive to an important family of anti-cancer drugs. The drugs, called thiopurines, cause serious side effects in these patients.

Researchers discovered that is because the patients were less able to break down the drugs. This, in turn, increased the risk that the drug would build up in the patients’ bodies.

The findings also helped explain why Asian and Hispanic patients often cannot tolerate thiopurines at standard doses. Researchers found that the high-risk versions of the gene are more common in people across Asia and those of Hispanic ancestry.

Understanding long-term effects of treatment

Lifesaving treatments for childhood brain tumors are a double-edged sword. While destroying cancer cells, therapy can also take a toll on the developing brain.

An unprecedented research study from St. Jude has shed new light on what this can mean for adult survivors of pediatric brain tumors. Researchers brought 224 survivors back to St. Jude, where they had been treated as children, for extensive testing and assessment.

While sobering, the results provided critical insights. Decades after treatment, many brain cancer survivors experienced deficits in intelligence, memory, educational achievement and employment. Radiation therapy to the brain and spine increased these risks, but was not the only contributing factor.

The findings will guide efforts to prevent and alleviate such problems in survivors. One key goal: Catch them early.

“We hope to help these kids while they are on therapy, to prevent the onset of some of these neurocognitive difficulties,” said Tara Brinkman, PhD, of St. JudeEpidemiology and Cancer Control. “For the survivors who have finished therapy, we want to develop ways to address the problems so they don’t become as severe as what we are seeing with our current adult survivors.”

The research, published in the Journal of Clinical Oncology, was part of the unique St. Jude LIFE study. The study brings childhood cancer survivors back to the hospital for regular health screenings throughout their adult lives.